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Publication numberUS3833595 A
Publication typeGrant
Publication dateSep 3, 1974
Filing dateAug 10, 1971
Priority dateDec 26, 1968
Publication numberUS 3833595 A, US 3833595A, US-A-3833595, US3833595 A, US3833595A
InventorsT Atsumi, K Kobayashi, Y Takebayashi, H Yamamoto
Original AssigneeSumitomo Chemical Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
2-aroylalkyl benzomorphans
US 3833595 A
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Description  (OCR text may contain errors)

United States Patent 3,833,595 Z-AROYLALKYL BENZOMORPHANS Toshio Atsumi, Kenji Kobayashi, and Yoshiaki Takebayashi, Takarazuka, and Hisao Yamamoto, Nishinomiya, Japan, assignors to Sumitomo Chemical Company, Limited, Osaka, Japan No Drawing. Continuation-impart of application Ser. No. 883,319, Dec. 8, 1969. This application Aug. 10, 1971, Ser. No. 170,640 Claims priority, application Japan, Dec. 26, 1968, 43/96,270, 43/96,271; Aug. 14, 1970, 45/71,637, 45/71,638; Sept. 17, 1970, 45/81,810, 45/81,811; Oct. 20, 1970, 45/92,611, IS/96,301; Dec. 8, 1910, 45/109,972, 45/109,973; Dec. 17, 1970, 45/114,363; Dec. 24, 1970, 45/130,369; Dec. 28,

1970, 46/129,967, 46/129,968; Jan. 29, 1971, 46/ 3,397; Dec. 1, 1971, 46/ 3,900

Int. Cl. C07d 39/00 US. Cl. 260--293.54 44 Claims ABSTRACT OF THE DISCLOSURE Benzomorphan derivatives of the formula:

a Ra R1 /(CH2)n-fi N 0 R; .wvRg lwvRs Rs I wherein R is a hydrogen atom, a C -C alkoxy group, an

acyloxy group, a hydroxy group, a nitro group, a halogen atom, a cyano group, an amino group, a carboxyl group, a carbamoyl group or a sulfo group; R is a hydrogen atom, a C -C alkyl group or a group of the formula, (C H )--(R (wherein m is an integer of 1-6; p is an integer of 1-2, and R is a hydroxyl group or a C -C alkoxy group); R is a hydrogen atom or a C C alkyl group; R and R, are independently a hydrogen atom, a halogen atom, a C -C alkyl group, a C C alkoxy group, a (l -C alkylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxyl group; R is a hydrogen atom or a methyl group; R is a hydrogen atom or a C --C alkyl group; R1; is a hydrogen atom, a C C alkyl group, a phenyl group or a 0-0 alkoxyphenyl group; R is a hydrogen atom or a hydroxyl group, or R and R may form a C -C alkylidene group or a carbonyl group together with a carbon atom to which these substituents are bonded; and n is an integer of 2-4, provided that, when n is an integer of 2, R and R are a methyl group, R is a hydrogen atom or a hydroxyl group and R R R R and R are hydrogen atoms, R, must be a halogen atom, a C -C alkyl group, a C -C alkoxy group, a C -C alkylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxyl group, which are useful as non-addicting, analgesic and pain-relieving agents with calming effect. These benzomorphan derivatives are prepared by reacting a 6,7-benzomorphan derivative of the formula:

ice

wherein R, R R R R R and R are as defined above, with a halogen derivative of the formula:

wherein R R and n are as defined above, X is a halogen atom and Y is an oxygen atom or an ethylenedioxy group, and further, in the case of Y=ethylenedioxy group, by hydrolyzing the resulting ethylenedioxy derivative of the formula:

wherein R, R R R R R R R R and n are as defined above.

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of co-pending application Ser. No. 883,319 filed on Dec. 8, 1969 and now abandoned.

The present invention relates to novel 6,7-benzomorphan derivatives and their salts and production thereof which are useful as non-addicted analgesics and pain-re lieving agents with calming effects.

Hitherto, many benzomorphan derivatives have been studied for developing new analgesics (see, for example, Belg. Pat. 611,000 or Chemistry of the Opium Alkaloids, US. Public Health Reports, Suppl. No. 103, Washington (1932)), but almost all of them produce addiction and other morphine-like side effects besides analgesic activity. These analgesics always produce significant physical dependency by administrating orally or subcutaneously. To our surprise, however, the present products do not show any drug dependency in animal tests.

One object of the present invention is to provide these novel benzomorphan derivatives which are useful as nonaddicted analgesics.

Another object of the present invention is to provide a process for producing these useful benzomorphan derivatives.

A further object of the present invention is to provide a novel pharmaceutical composition containing these useful benzomorphan derivatives.

Other object and advantages of the present invention will be apparent from the following description.

In order to accomplish these objects, the present invention provides novel benzomorphan derivatives of the formula,

Patented Sept. 3, 1974 wherein R is a hydrogen atom, a C -C alkoxy group, an

acyloxy group, a hydroxyl group, a nitro group, a halogen atom, a cyano group, an amino group, a carboxyl group, a carbamoyl group or a sulfo group; R is a hydrogen atom, a C -C alkyl group or a group of the formula, (C H )--(R (wherein m is an integer of l-6; p is an integer of 1-2, and R is a hydroxyl group or a C -C alkoxy group); R is a hydrogen atom or a C -C3 alkyl group; R and R are independently a hydrogen atom, a halogen atom, a C -C alkyl group, a C -C alkoxy group, a C C alkylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxyl group; R is a hydrogen atom or a methyl group; R is a hydrogen atom or a C -C alkyl group; R is a hydrogen atom, a (E -C alkyl group, a phenyl group or a C -C alkoxyphenyl group; R is a hydrogen atom or a hydroxyl group, or R and R may form a C -C alkylidene group or a carbonyl group together with a carbon atom to which these substituents are bonded; and n is an integer of 2-4, provided that when n is an integer of 2; R and R are methyl groups; R is a hydrogen atom or a hydroxyl group; R R R R and 'R are hydrogen atoms, R must be a halogen atom, a C -C alkyl group, a C -C alkoxy group, a C -C al'kylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxy group.

The present invention further provides a process for producing benzomorphan derivatives of the formula I, which comprises hydrolyzing an ethylenedioxy derivative of the formula:

wherein R, R R R R R and R are as defined above, with a reactive halide of the formula:

wherein R R and n are as defined above; X is a halogen atom and Y is an oxygen atom or an ethylenedioxy group,

4 and further, inthe case of Y=ethylenedioxy, hydrolyzing the resulting ethylenedioxy derivative of the formula II).

The present invention still further provides novel pharmaceutical composition consisting of an analgesically effective amount of a benzomorphan derivative of the formula (I) as active ingredient and pharmaceutically acceptable carrier or diluent.

The starting materials of this invention, 6,7-benzomorphan derivatives of the formula (III) are prepared from the corresponding 2-methyl 6,7 benzomorphan derivatives by demethylation. Thus, for example, US. Patent Specification No. 3,138,603 discloses a process shown by the following scheme.

CH3 CH3 1 BrCN Q g H3 /N N d 11h H3 wherein R is methoxy group or acetoxy group.

Further, several processes have heretofore been described for the production of 2-methyl 6,7 benzomorphan derivatives represented by the general formula:

wherein R is a hydrogen atom, a methoxy group, a hydroxyl group, an acetoxy group, a nitro group, an amino group or a halogen atom; R is a hydrogen atom, a lower alkyl group, an alkoxy or hydroxyalkyl group; R is a hydrogen atom or a lower alkyl group; R is a hydrogen atom or a methyl group; R is a hydrogen atom or an alkyl group; R is a hydrogen atom, a methyl group or a phenyl group; and R is a hydrogen atom or a hydroxyl group or R and R may form carbonyl group or a methylene group together with a carbon atom to which these substituents are bonded, as shown in scheme 1 and scheme 2.

wherein R, R R R R R and R are as defined above and X is a halogen atom, and another process is described as follows:

R1 CHzCHzN l R R wherein R is a hydrogen atom, a methoxy group or a hydroxy group; R is a hydrogen atom of a methyl group; and R is a hydrogen atom or a methyl group.

Further, when R is a cyano group, a carboxyl group, a carbamoyl group or a sulfo group, such 2-methyl-6,7- benzomorphan derivatives [V] are prepared from the corresponding 2-amino-derivatives via diazonium derivatives as follows:

wherein R is a cyano group, a carboxyl group, a carbamoyl group or a sulfo group; and R R R R R and R are as defined above.

The reaction of a 6,7-benzomorphan derivative [III] with a reactive halide [IV] is usually accomplished in an organic inert solvent, for example, n-hexane, benzene,

toluene, xylene, chloroform, dimethylformamide, methanol, ethanol, isopropylalcohol, and the like. The reaction is preferably carried out in the presence of a base, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride,

1 1 2'Fluoro-2- [4"- (p-fluorophenyl) -4",4"-ethylenedioxy- 1"-butyl] -5,9-dimethyl-6,7-benzomorphan 2'-Nitro-2- [3 (p-fluorophenyl) -3 ",3 '-ethylenedioxy- 1-propyl] -6,7-benzomorphan Moreover, according to the above process, when 2- methyl-6,7-benzomorphan derivatives [v] obtained by the process of (vi) Deutsche Offenlegungsschrift 2002864, and (vii) Albert Ziering (Journal of Medicinal Chemistry, 13, 9 (1970)) are used as the starting material in the present invention, the following 6,7-benzomorphan derivatives are obtained,

wherein R is a hydrogen atom, a C -C alkoxy group, a hydroxyl group or an acyloxy group; and R R R R R R R R n and Y are as defined above.

2- [4"- (p-Fluorophenyl -4",4"-ethylenedioxy- 1 butyl] -5,8,9-trimethyl-6,7-benzomorphan 2-Hydroxy-2- [4"- (p-fiuorophenyl) -4",4"-ethylenedioxy- 1"-butyl] -5,8,9-trimethyl-6,7-benzomorphan 2'-Hydroxy2- [4"- (p-fluorophenyl) -4,4-ethylenedioxy- 1"-butyl] -5,8-dimethyl-6,7-benzomorphan 2'-Hydroxy-2-[4" (p-fluorophenyl) -4",4"-ethylenedioxy- 1"-butyl] -8-methyl-6,7-benzomorphan 2'-Hydroxy-2- [3 (p-fluorophenyl -3 ,3"-ethylenedioxy- 1"-propyl] -5,8,9-trimethyl-6,7-benzomorphan 2'-Hydroxy-3 '-methyl-2- [4"- (p-fluorophenyl) -4",4"-

ethylenedioxy-l "-butyl] -5,9-dimethy1-6,7- benzomorphan 2'-Hydroxy-2- [4- (p-methoxyphenyl -4",4"-ethylenedioxy- 1 "-butyl] -3,S-dimethyl-6,7-benzomorphan 2'-Hydroxy-2- [4"- p-fluorophenyl) -4",4 '-ethylenedioxy-1"-butyl]-5-methy1-8-oxo-6,7-benzomorphan 2'-Hydroxy-2- [4"- (p-fluorophenyl -4",4-ethylenedioxy-1"-butyl] -5 ,9-dimethyl- 8-methylene-6,7- benzomorph an 2-Hydroxy-2- -benzoyl-n-propyl) -5,8,9-trimethyl- 6,7-benzomorphan 2'-Hydroxy-2- [4- (p-fluorophenyl) -4,4-ethylenedioxy-1"-butyl] -3,5-dimethyl-6,7-benzomorphan 2'-HydroXy-3 -methyl-2- [4- (p-fluorophenyl) -4,4"-

ethylenedioxy- 1 -butyl] -6,7-b enzomorphan 2'-Hydroxy-2- [4"- 3,4-dimethoxyphenyl -4",4"- ethylenedioxy-1"-butyl] -5,8,9-trimethyl-6,7- benzomorphan 2'-Hydroxy-2- [3 (p-methoxyphenyl) -3 ",3 "-ethylenedioxy-1"-propyl] -5,8,9-trimethyl-6,7-benzomorphan Moreover, according to the above process, when 2- methyl 6,7 benzomorphan derivative [V] obtained by the process of (viii) Everret L. May (Journal of Organic Chemistry, 25, 1386 (1960)) are used as the starting material in the present invention, the following 6,7-benzomorphan derivatives are obtained,

2-Hydroxy-2- 5 p-fluorophenyl) -5 ",5 "-ethy1enedioxy- 1' -pentyl] -9-methyl-6,7-benzomorphan 2'-Hydroxy-2- [4"- (p-trifluoromethylphenyl) -4",4"-

ethylenedioxy- 1 -butyl] -9-methyl-6,7-benzomorphan 2'-Hydroxy-2- *y-benzoyl-n-propyl) -9-methyl-6,7-

benzomorphan 2-Hydroxy-2- [4"- (p-rnethoxyphenyl -4",4"-ethylenedioxy-1"-butyl]-9-rnethyl-6,7-benzomorphan 2- [4"- (p-Fluorophenyl) -4",4-ethylenedioxy-1"-butyl]- 9-methyl-6,7-benzomorphan 2- [4-(p-Methoxyphenyl) -4",4"-ethylenedioxy-1"- butyl] -9-methyl-6,7-b enzomorphan 2- ('y-Benzoyl-n-propyl -9-methyl-6,7-benzomorphan 2'-Hydroxy-2- 3 (p-fluorophenyl -3 ",3"-ethylenedioxy- 1 "-propyl] -9-methyl-6,7-benzomorphan 2- [3 (p-Fluorophenyl) -3 -ethylenedioxy-l propyl] -9-methyl-6,7-benzomorph an 2'-Hydroxy-2- [3 (p-methoxyphenyl) -3",3 "-ethylenedioxy-l -propyl] -9-methyl-6,7-benzomorphan 2- [3 (p-Methoxyphenyl -3 ",3 "-ethylenedioxy-1"- propyl] -9-methyl-6,7-b enzomorphan 2'-Hydroxy-2- 3-b enzoylethyl -9 -1nethyl-6,7-b enzomorphan 2-Hydroxy-2- [4"- 3 ,4-dimethoxyphenyl) -4",4"-ethylenedioxyl '-butyl] -9-methyl-6,7-benzomorphan In the present invention, an ethylenedioxy derivative [II] mentioned above is converted to a desired 6,7-benzomorphan derivative [I] by hydrolyzin-g in the presence of an acid.

The hydrolysis of the said ethylenedioxy derivative [H] is carried out in a suitable solvent, for example, water, an alcohol such as methanol, ethanol, nor iso-propanol, n-butanol and the like, preferably at a temperature ranging from room temperature to the boiling point of the solvent used. In this reaction employment of a catalytic amount of acid is necessary, examples of which include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and acetic acid and the like. The reaction is usually completed after 0.5 to 2 hours.

When Z-substituted 6,7-benzomorphan derivative of the formula [I] (R is an acyloxy group) is desired, the purpose is easily performed by acylating the compound of the formula [I] (R is a hydroxyl group) with an acid anhydride or an acyl halide.

The thus prepared 6,7-benzomorphan derivative [I] may be converted into its acid-addition salt by conventional procedures, e.g. treatment with an organic or inorganic acids such as formic acid, acetic acid, butyric acid, malic acid, fumaric acid, succinic acid, glutamic acid, tartaric acid, oxalic acid, citric acid, lactic acid, glycolic acid, gluconic acid, glucuronic acid, saccharic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, glyceric acid, anthranilic acid, cholic acid, picolinic acid, picric acid, tropic acid, indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like.

According to the process of the present invention, there are produced such 6,7-benzomorphan derivatives as shown below.

2'-Hydroxy-2- ['y- (p-fluorobenzoyl) -n-propyl]-5,9-

dimethyl-6,7-benzomorphan 2'-Hydroxy-2- ['y-p-fluorob enzoyl -n-propyl -5,9-

dimethyl-6,7-benzom orphan 2-Hydroxy-2- ['y- (m-fluorob enzoyl) -n-propyl] -5,9'-

dimethyl- 6 ,7 -benzornorphan 2'-Hydroxy-2- ['y- (p-fiuorophenyl -n-butyl] -5,9-

dimethyl-6,7-benzomorphan 2'-Hydroxy-2- ['y- (p-trifluoromethylbenzoyl -n-propyl] 5,9-dimethyl-6,7-benzomorphan 2'-Hydroxy-2- ['y- (m-trifluoromethylbenzoyl )n-propyl 5-methyl-9-ethyl-6,7-benzomorphan 542m N (5H.

i E CH2 Step 1 a N l: 5(CHa I N02 Step 2 Step3 ('IJHa N (CH:

About this process, the present inventors demonstrated in detail in Example 41.

Thus obtained cisand trans-6,7-benzomorphan derivatives (V) are separated and purified by the above-mentioned methods, and then converted to starting materials, cisor trans-6,7-benzomorphan derivatives III by demethylation. Furthermore, each of these stereo isomers has asymmetric carbon atoms, so that there are obtained four difierent kinds of optical active 6,7-benzomorphan derivatives (I), i.e. (+)-cis, ()-cis, (+)-trans, trans isomers by a conventional optical resolution method.

6,7-Benbomorphan derivatives such as 2-hydroXy-2,5,9- trimethyl-6,7-benzomorphan (US. Pat. No. 3,138,603) have a potent analgesic activity, but show an addiction liability. On account of this addiction liability, these analgesics are severely restricted in a therapeutic use. Surprisingly, as shown in Table 1, the present 6,7 benzomorphan derivatives (I) do not show any addiction liability syndrome in detailed animal tests. For example, when these present compounds were administered orally or subcutaneously to animals every day for a long term, the animals did not produce any physical dependency.

TABLE 1.CHRONICAL ADMINISTRATION TEST IN RAT$ DOE: Ab ti m s S.C /d a nence Compound for 4 weeks) syndrome 5-methyl-9-ethyl-6,7-benzomorphan 20 2-Hydroxy-2-[v-(p-fluorobenzoyl)-n-propyl]- 6,7-benzomorphan 20 2-['y-(p-fluorobenzoyl)-n-propyl]-5-methylbenzomorphan 20 a-2-hydroxy-2-('ybenzoyl-n-pr0pyl)-5,9

dimethyl-6,7-benzomorphan 20 a-2-hydr0Xy-2,5,9-trimethyl6,7-

benzomorphan 20 Morphine 20 1 8.0. means subcutaneous injection.

NoTE.Rat: Wistar strain, T, g. body weight at the beginning of the test; each group consists of 20 animals.

Furthermore, the present 6,7 benzomorphan derivatives [I] have mild or strong analgesic activity in a subcutaneous writhing test, and some of them have shown potent analgesic action, which potencies are much greater than that of pentazocine, the first class nonnarcotic analgesic. (Table 2) The method is based on the specific antagonism of analgesics to the typical syndrome produced by intraperitoneal injection of 0.6% of aqueous acetic acid. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of trunk and extensionof hind legs.

A group of 5 mice was used for each dose level. Compounds were administered subcutaneously 20 minutes before injection of acetic acid. Number of mice which showed no pain response was recorded. ED was calculated according to the Litchfield-Wilcoxons method.

TABLE 2 Efiect in subcutaneous writhing Compound: test (EDs mg./kg.

2' Hydroxy 2 ['y (p fluorobenozyl) 11- propyl] 5,9-dimethyl-6,7-benzomorphan 2 Hydroxy 2- ['y (p fiuorobenzoyl) n propyl] 5 methyl-9-ethyl-6,7-benzomorphan 2 Hydroxy 2 ['y (p methoxybenzoyl) n propyl] 5 methyl 9 ethyl 6,7 benzomorphan 2' Hydroxy 2 ['y-(3,4-dimethoxybenzoyl)- n-propyl]5,9-dimethyl-6,7-benzomorphan 2 ['y (p Flu0robenzoyl)-n-propyl] 5,9 dimethyl 6,7 benzomorphan 2 Hydroxy 2- ['y (p-methoxybenzoyl) n propyl] 5,9-dimethyl-6,7-benzomorphan 2 Hydroxy 2 ('y benzoyl n propyl) 5,9 dimethyl 6,7 benzomorphan a 2' Hydroxy 2 ('y benzoyl n propyl)- 5 methyl 9 ethyl 6,7 benzomorphan 2 Hydroxy 2 ['y (p fiuorobenzoyl) n propyl] 5 methyl 6,7-benzomorphan 2 Hydroxy 2 ['y (p fiuorobenzoyl) n propyl] 6,7 benzomorphan B 2' Hydroxy 2 ['y (p-fluorobenzoyl)-npropyl] 5,9-dimethyl-6,7-benzomorphan a 2' Hydroxy 2 [[3 (p fiuorobenzoyl)- ethyl] 5,9 dimethyl 6,7-benzomorphana 2' Methoxy 2 ['y (p fiuorobenzoyl)- n-propyl]-5,9-dimethyl-6,7-benzomorphan 2 Hydroxy 2 -[B (p-fluorobenzoyl)ethyl]- 6,7 benzomorphan 2 ('y Benzoyl n propyl) 5 methyl 6,7-

benzomorphan 19 TABLE 2Continued Effect in subcutaneous writhing Compound: test (ED mg./kg.

a 2' Hydroxy 2 [fi-(p-methoxybenzoynethyl] 5,9 dimethyl 6,7-benzomorphan 7.0 a 2' Acetoxy 2 ['y (p fluorobenzoyl)- n-propyl]-5,9-dimethyl-6,7-benzomorphan 7.0 2 ['7 (p Fluorobenzoyl) n propyl] 5 methyl 6,7 benzomorphan 6.0 2 ['y (p Fluorobenzoyl) n propyl]-6,7-

benzomorphan 7.0 a 2' Hydroxy 2 ['y (p fluorobenzoyl)- n propyl] 5,8,9 trimethyl 6,7-benzomorphan 12.0 a 2' Hydroxy 3' methyl 2 ['y (pfiuorobenzoyl) n propyl] 5,9 dimethyl- 6,7 benzomorphan 17.0 a 2 Hydroxy 2 ['y (m fiuorobenzoyD- r1 propyl] 5,9 dimethyl 6,7 benzomorphan 12.0 Pentazocine (2' hydroxy 2 (3" methyl- 2" butenyl) 5,9 dimethyl 6,7- benzomorphan) 17.5

Among these compounds, some compounds are shown to have potent analgesic effect not only in this writhing test, but also other analgesic tests, for example, a hot plate test, and Hoifner method test. Moreover, as shown in Table 3, the present compounds have a mild calming effect, which effect sometimes boosts the analgesic elfect.

TABLE 3 Tranquilizing Activity Test in Rats (Anti-Apomorphine Test) ED on anti-apomorphine Compound: test (mg/kg. S.C.) a 2' Hydroxy 2 ['y (6-fluorobenzoyl)-npropyl]5,9 dimethyl-6,7-benzomorphan 84.0 2' Hydroxy 2 ['y (p fluorobenzoyl) npropyl] 5 -methyl 6,7-benzomorphan 70.0 Haloperidol* 0.08

*Haloperldol is a representative tranquilizer.

Nora-Rat: Wistar strain, d, 150-180 g. body weight; each group consists of 100 animals.

Moreover, these present compounds have not any unfavorable side effects, for example, rigidity, ataxia, convulsion, emetic activity and respiratory depression, etc., unlike other morphine and 6,7-benzomorphan derivatives.

As shown in Tables 4 and 5, the present compounds showed no respiration depressing activity and no emetic activity. This is also a prominent characteristic of the present compounds.

I.m. means intramuscular injection.

NoTn.-Dog: Beagel strain, a, 812 kg. body weight; each group consists of 10 animals.

No'rn.Dog: Beagle strain, 6, 8-12 kg. body weight; each group consists of 10 animals.

As shown in Table 6, morphine and other benzomorphan derivatives have not any local anesthetic ac tivity, but the present compounds showed a potent local anesthetic activity. This is also a prominent characteristic of the present compounds.

TABLE 6.LOCAL ANESTHETIC ACTIVITY TEST Local anesthetic activity in Concenguinea pig,

tration, intradermal Compound percent method a-2-hydroxy-2-['y-(p'fluorobenzoyD-n- 1 pgopyl1-5, EJ-dimethyl-G, 7-benzom0rp an. 2-hydroxy-2-[-y-(p-fluorobenzoyl)-n- 1 propyl]-S-methyHi, 7benzomorpl1an. 2-hydroxy-2-[ -(p-fiuorobenzoyl)-nl propyl]-6, 7-benz0morphan. 01-2 -hydroxy-2, 5, Q-trimethyHi, 7-benzomorphan. 1 Morphine 1 Xylocaine 1 Procaine 1 No'rn.Guinea pig: Hartley strain, (5, 250-300 g. body weight each group consists of 3 animals.

The above-mentioned prominent characteristics of the present compounds, that is, no addiction liability, no respiratory depression, no emetic activity, a potent analgesic activity, a potent local anesthetic activity and a mild tranquilizing activity are attributed to 2-aroylalkyl-substituted 6,7-benzomorphan and cannot be seen in morphine and other 6,7-benzomorphan derivatives.

The compounds can be prepared for use by dissolving under sterile conditions a salt form of the compounds in water (or an equivalent amount of a non-toxic acid if the free base is used), or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for use by injection.

Alternatively, the compounds can be incorporated in unit dosage (1-15 mg.) form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like.

The following examples are representative of the methods of production of the compounds. Modifications of these procedures will be obvious to those skilled in the art and these examples are not to be construed as limiting the scope of this invention.

EXAMPLE 1 2'-Hydroxy-2- ['y- (p-fluorobenzoyl) -n-propyl] 5 ,9-dimethyl-6,7-benzomorphan (a) 2'-Hydroxy 2 [4"- (p-fiuorophenyl)-4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7-benzomorphan: To a mixture of 1.08 g. of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 0.6 g. of sodium bicarbonate and 15 ml. of dimethylformamide is added 1.43 g. of 4-(p fluorophenyl)-4,4-ethylenedioxy-l-bromobutane. The resultant lavggg z 1005, 1582, 1500, 1210, 1147, 1048, 830

Anal.-Calcd. for C H NO F: C, 73.38; H, 7.58; N, 3.29%. Found: C, 73.51; H, 7.62; N, 3.25%.

(b) 2'-Hydroxy-2- ['y-(p-fiuorobenzoyl)-n-propyl] 5,9- dimethyl-6,7-benzomorphan: A mixture of 2.4 g. of 2'- hydroxy 2 [4"- (p-fluorophenyl) 4",4-ethylenedioxyn-butyl] 5,9-dimethyl-6,7-benzomorphan, 20 ml. of methanol, ml. of water and 1.5 ml. of concentrated hydrochloric acid is refluxed for 1 hour. After the reaction mixture is concentrated under reduced pressure, the mixture is made alkaline with excess aqueous ammonia, and is extracted with ether. The ether extracts are washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness to give the crude compound. Recrystallization from ethyl acetate gives 2'-hydroxy-2-[*y-(p-fluorobenzoyl) n-propyl] 5,9-dimethyl 6,7-benzomorphan, m.p.: l66-169 C.

2000 (broad), 1900, 1598, 1582, 1222, 840,

m g-Q 2580, 2550, 1090, 1020, 1599, 1585, 1504, 1210, 1204, 1148, 831

Anal.Calcd. for C H NO ClF: C, 68.97; H, 6.99; N, 3.35; Cl, 8.48%. Found: C, 68.98; H, 7.19; N, 3.63; Cl, 8.27%.

EXAMPLE 2 2- [7- (p-Fluorobenzoyl)-n-propyl]-5,9-dimethyl- 6,7-benzomorphan (a) 2 [4"-(p-Fluorophenyl) 4,4"-ethylenedioxy-nbutyl]-5,9-dimethyl 6,7-benzomorphan: A mixture of 3 g. of 5,9-dimethyl-6,7-benzomorphan, 1.89 g. of sodium bicarbonate, 4.29 g. of 4-(p-fiuorophenyl)-4,4-ethylenedioxyl-l-chlorobutane and 30 ml. of ethanol is heated under reflux with stirring for 6 hours. This mixture is concentrated under reduced pressure until most of the ethanol has been removed, and water is added thereto. The mixture is extracted several times with ether. The combined extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the residue is distilled under reduced pressure to give 4.75 g. of 2-[4-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl] 5,9-dimethyl 6,7- benzomorphan, b.p.: 110-1l9 C./O.8 mm. Hg.

IRvffi 1605, 1508, 1217, 1150, 1040, 835

(b) 2 ['y-(p-Fluorobenzoyl)-n-propyl] 5,9-dimethyl- 6,7-benzomorphan: To a mixture of 4.7 g. of 2-[4"-(pfiuorophenyl)-4",4"-ethylenedioxy-n-butyl] 5,9-dimethyl-6,7-benzomorphan, 50 ml. of methanol and 30 ml. of water is added 5 ml. of concentrated hydrochloric acid. After the resultant mixture is refluxed for 1 hour, the mixture is concentrated under reduced pressure to residue, which is made alkaline with an aqueous ammonia and extracted with ether. The ether extract is washed with water saturated with sodium chloride, dried over anhydrous 22 sodium sulfate, and filtered. The filtrate is concentrated to a yellow residue, which is distilled under reduced pressure to yield 1.5 g. of 2-[y-(p fluorobenzoyl)-n-propyl]- 5,9-dimethyl-6,7-benzomorphan, b.p.: -l50 C./0.5- mm. Hg.

IRvfi 1690, 1601, 1510, 1220, 835, 760, 720

A solution of 2-[' -(p-fluorobenzoyl)-n-propyl]-5,9-dimethyl-6,7-ber1zomorphan in ether is acidified with gaseous hydrogen chloride. The precipitate produced is collected by filtration and washed with ether.

Recrystallization from ether-acetone gives 2 ['y (pfluorobenzoyl)-n-propyl] 5,9-dimethyl 6,7-benzomorphan hydrochloride, m.p.: 164 166 C.

111112 353, 2350 (broad), 1680, 1000, 1508, 832, 760,

Anal.-Calcd. for C H NOClF: C, 71.72; H, 7.27; N, 3.48; CI, 8.82%. Found: C, 71.42; H, 7.40; N, 3.39; Cl, 8.77%.

EXAMPLE 3 2-Hydroxy-2- ['y- (p-fluorobenzoyl)n-propyl] S-methyl-9-ethyl-6,7-benzomorphan (a) 2'-Hydroxy 2 [4"- (p-fiuorophenyl) 4",4"-ethylenedioxy-n-butyl] 5 methyl-9-ethyl 6,7benzomorphan: According to the procedure of Example 1(a), the reaction of 2.31 g. of 2'-hydroxy-5-methyl-9-ethyl-6,7 benzomorphan with 2.56 g. of 4-(p-fluorophenyl)-4,4-ethylenedioxy-l-chlorobutane gives 2'-hydroxy 2 [4"-(pfluorophenyl) 4",4"-ethylenedioxy-n-butyl] 5 methyl- 9-ethyl-6,7-benzomorphan, m.p.: 161167 C.

Recrystallization from ethyl acetate causes raising of the melting point to l70l71 C.

meg-g 1515, 1605, 1579, 835, 794

Anal.-Calcd. for C2qH34NO3F: C, 73.77; H, 7.80; N, 3.19%. Found: C, 73.58; H, 7.78; N, 3.52%.

(b) 2-Hydroxy 2 ['y-(p-fiuorobenzoyl)-n-propyl]- S-methyl-9-ethy1-6,7benzomorphan: According to the procedure of Example 1(b), 2-hydroxy-2-[4-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl] 5 methyl 9 ethyl- 6,7-benzomorphan converts to 2'-hydroxy-2- ['y (p-fiuorobenzoyl)-n-propyl] 5 methyl-9-ethyl-6,7-benzomorphan hydrochloride, m.p.: 165 C.

lava-3, 1620, 1720, 1597, 1582, 1500, 838

Anal.-Calcd. for C H NO ClF: C, 69.82; H, 7.23; N, 3.24%. Found: C, 69.78; H, 7.29; N, 3.29%.

EXAMPLE 4 2'-Hydroxy-2- [6- (p-chlorobenzoyl) -n-propyl] -5,9-dimethyl-6,7-benzomorphan Anal.-Calcd. for C H NOCl: C, 70.65; H, 7.30; N, 3.17; CI, 8.02%. Found: C, 70.65; H, 7.27; N, 3.14; Cl, 8.23%.

(b) 2'-Hydroxy 2 ['y (p chlorobenzoyl-n-propyl]- 5,9-dimethyl-6,7-benzomorphan: To a mixture of 3.65 g.

2650 (broad), 1620, 1603, 1585, 1495, 1225,

IRv 2600 (broad), 1690, 1625, 1590, 1495, 1235, 121 1083, 766

Anal.Calcd. for C H NO Cl: C, 72.44; H, 7.09; N, 3.52; Cl, 8.91%. Found: C, 72.17; H, 7.25; N, 3.89; Cl, 8.86%.

The free base is converted to the hydrochloride by contacting with dry gaseous hydrogen chloride. The precipitate is collected by filtration and washed with ether. Recrystallization from methanol-acetone gives 2'-hydroxy- 2- ['y-(p chlorobenzoyD-n-propyl]-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p.: 191-192 C.

Anal.Calcd. for C H NO Cl: C, 66.36; H, 6.73; N, 3.22; CI, 16.32%. Found: C, 65.86; H, 6.96; N, 3.52; C1, 16.73%.

EXAMPLE 5 2-Hydroxy-2- ['y- (p-methoxybenzoyl -n-propyl]-5,9-dimethyl-,7-benzomorphan (a) 2'-Hydroxy-2-[4"-(p methoxyphenyl)-4,4"-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7-benzomorphan: To a solution of 2.17 g. of 2'-hydroxy-5,9-dimethyl-6,7-benzo morphan in 30 ml. of dimethylformamide are added 1.2 g. of sodium bicarbonate and 2.7 g. of 4- (p-methoxyphenyl)-4,4-ethylenedioxy 1 chlorobutane. The mixture is stirred at 120-140 C. for two hours. The solvent is evaporated under reduced pressure, and water is added thereto. After the mixture is allowed to stand in the refrigerator, the precipitate produced is collected and recrystallized from ethyl acetate to yield 2-hydroxy-2-[4"- (p methoxyphenyl)4",4"-ethylenedioxy-n-butyl] -5,9-dimethyl-6,7-benzomorphan, m.p.: 156158.5 C.

rnvggg z 2650 (broad), 1615, 1580,1515, 1500, 1245, 1050, 830

Anal.Calcd. for C2'1H35NO4Z C, 74.11; H, 8.06; N, 3.20%. Found: C, 73.74; H, 8.20; N, 3.60%.

(b) 2'-Hydroxy-2-[' -(p methoxybenzoyl)-n-propyl]- 5,9-dimethyl-6,7-benzomorphan: To a mixture of 2.0 g. of 2-hydroxy-2-[4"- (p methoxyphenyl)-4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7-benzomorphan, 20 ml. of methanol and ml. of water is added 1.5 ml. of concentrated hydrochloric acid. The mixture is heated with stirring for one hour. The reaction mixture is concentrated under reduced pressure to remove the methanol and made alkaline with an aqueous ammonia. The solution is extracted with chloroform. The extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent is removed to give the crude product. Recrystallization from ethyl acetate gives 2'-hydroxy-2- ['y- (p-methoxybenzoyl)-n-propyl]- 5,9-dimethyl-6,7-benzomorphan, m.p.: 148-152.8 C.

mpg-g 2650 (broad), 1680, 1600, 1580, 1.500, 1255, 1160, 1020, 820, 760

Anal.Ca1cd. for C H NO C, 76.30; H, 7.94; N, 3.56%. Found: C, 76.16; H, 7.88; N, 3.42%.

EXAMPLE 6 2-Hydroxy-2- ['y-(p-methylbenzoyl) -n-propyl] -5,9- dimethyl-6,7-benzomorphan (a) 2'-Hydroxy-2- [4"- (p-methylphenyl) -4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl 6,7-benzomorphan: According to the procedure of Example 1(a), but using 2.17 g. of 2'-hydroxy-5,9-dimethyl-6,7-benzom0rphan, 1.2 g. of sodium bicarbonate, 30 ml. of dimethylformamide and 2.06 g. of 4-(p-methylphenyl)-4,4-ethylenedioxy-1- chlorobutane, there is produced crude 2-hydroxy-2-[4"- (p-methylphenyl)-4",4"-ethylenedioxy n butyl]-5,9'-dimethyl-6,7-benzomorphan. Recrystallization of the crude product from ethyl acetate yields pure crystals of 2.- hydroxy-2-[4"- (p methylphenyl) 4",4"-ethylenedioxyn-butyl]-5,9-dimethyl-6,7-benzomorphan having a melting point of 173 to 176 C.

IRv; g 2650 (broad), 1615, 1580, 1505, 1240, 1050, 820

Anal.Calcd. for C H -NO C, 76.92; H, 8.37; N. 3.32%. Found: C, 76.84; H, 8.55; N, 3.82%.

(b) 2'-Hydroxy-2-['y (p methylbenzoyD-n-propyl]- 5,9-dirnethyl-6,7-benzomorphan: According to the procedure of Example 1(b), but using 2.5 g. of 2'-hydroxy- 2-[4"-(p-methylphenyl) 4",4" ethylenedioxy-n-butyl1- 5,9-dimethyl-6,7-benzomorphan, there is produced a crude compound which is recrystallized from ethyl acetate to give pure crystals of 2'-hydroxy-2-['y-(p-methylbenzoyD- n-propyl]-5,9-dimethyl-6,7-benzomorphan, m.p.: 157.5"- 164.5 C.

1119 3 351, 2600 (broad), 1683, 1610, 1580, 1498, 1233, 800, 765

Anal.Calcd, for C H NO C, 79.53; H, 8.28; N, 3.71%. Found: C. 79.45; H, 8.29; N, 3.80%.

EXAMPLE 7 2'-Hydroxy-2-['y-(p-trifiuoromethylbenzoyl)-n-propyl] -5,9-dimethyl-6,7-benzomorphan A mixture of 1.19 g. of 2-hydroxy-5,9-dimethyl-6,7- benzomorphan, 0.6 g. of sodium bicarbonate, 1.77 g. of 4-(p-trifluoromethylphenyl)-4,4-ethylenedioxy l-chlorobutane and 15 ml. of dimethylformamide is stirred at -145 C. for three hours. This reaction mixture is concentrated under reduced pressure until most of the dimethylformamide has been removed, and water is added thereto and, it is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is treated with decolorizing charcoal and concentrated under reduced pressure. The residual oil is dissolved in hot aqueous methanol and the solution is treated with concentrated hydrochloric acid to pH 1. After the solution is refluxed for one hour, the solution is treated with charcoal and filtered. After the filtrate is concentrated under reduced pressure, it is made alkaline with an aqueous ammonia and extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to an amorphous residue. This residue is chromatographed on a silica gel column with ethyl acetate to give the crude product. This compound is recrystallized from ethyl acetate to yield 2'-hydroxy-2-[v-(p-trifluoromethylbenzoyl)-n-propyl]-5,9 dimethyl-6,7-benzomorphan, m.p.: 116.5120 C.

Anal.Calcd. for C H NO F C, 69.59; H. 6.54; N, 3.25%. Found: C, 69.81; H, 6.73; N, 3.40%.

25' EXAMPLE 8 -Hydroxy-2- ['y- (p-methoxybenzoyl) -n-propyl] methyl-9-ethyl-6,7-benzomorphan (a) 2'-Hydroxy-2- [4"- (p-methoxyphenyl) -4,4"-ethylenedioxy-n-butyl]-5-methyl 9-ethyl-6,7-benzomorphan: According to the procedure of Example 5(a), the reaction of 2,'-hydroxy-5-methyl-9-ethyl-6,7-benzomorphan (2.3 g.) with 2.7 g. of 4-(p-methoxyphenyl)-4,4-ethylenedioxy-l-chlorobutane gives 2-hydroxy-2-[4"-(p-methoxyphenyl)-4",4"-ethylenedioxy n-butyl] 5-methyl-9-ethyl- -6,7-benzomorphan, m.p.: 140-142 C.

IRwg 2650, 2550, 1613, 1580, 1510, 1497, 1252, 1053, 1038, 836

Anal.Ca1cd. for C H NO C, 74.47; H, 8.26; N, 3.10%. Found: C, 74.69; H, 8.24; N, 3.43%.

(b) 2'-Hydr0xy 2-[' -(p-methoxybenzoyl)-n-propyl]- 5-methyl-9-ethyl-6,7-benzomorphan: By subjecting 2-hydroxy-Z-[4"-(p-methoxyphenyl) 4",4" cthylenedioxyn-butyl]-5-methyl-9-ethyl-6,7-benzomorphan to the procedure of Example 5(b), there is produced a crude product, which is recrystallized from methanol-acetone to yield pure crystals of 2'-hydroxy-2-[' -(p-methoxybenzoyl)-npropyl] -5-rnethyl-9 ethyl-6,7-benzomorphan hydrochlo ride, m.p.: 148-150.0 C.

mug-3 1675, 1612, 1598, 1570, 1510, 1504 AnaL-Calcd. for C -H 'NO Cl: C, 70.33; H, 7.72; N, 3.15%. Found: C, 70.14; H, 7.77; N, 3.14%.

EXAMPLE 9 2'-Hydroxy-2- [6- (p-fluorobenzoyl -n-butyl] -5,9- dimethyl-6,7-benzomorphan A mixture of 2.17 g. of 2'-hydroxy-5,9-dimethyl-6,7- beu'zomorphan, 1.26 g. of sodium bicarbonate, 3.88 g. of 5-(p fluorophenyl)-5,5-ethylenedioxy-l-chloropentane and 30 ml. of dimethylformamide is stirred at 125-130 C. for four hours. The mixture is concentrated under reduced pressure until the dimethylformamide has been removed, and water is added thereto and it is extracted with ether. The extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to dryness. The residue obtained is used without purification. To a mixture of 4.0 g. of crude 2'-hydroxy-2-[5"-(p-fiuorophenyl)-5,5"- ethylenedioxy-n-pentyl] 5,9-dimethyl-6,7-benzomorphan, 50 ml. of methanol and 30 ml. of water is added 5 ml. of concentrated hydrochloric acid. The mixture is boiled for one hour, treated with decolorizing charcoal and hotfiltered. The filtrate is evaporated to dryness under reduced pressure. Trituration of the residue with ether gives crude 2-hydroxy 2- [6- (p-fluorobenzoyl) n-butyl] -5,9-dimethyl-6,7-benzomorphan hydrochloride. Recrystallization from methanol-acetone affords pure crystals of 2'- hydroxy-Z-[6-(p-fluorobenzoyl) n butyl]-5,9-dimethyl- 6,7-benzomorphan hydrochloride, m.p.: 229231 C.

Anal.Calcd. for C H NO ClF: C, 69.51; H, 7.25; N, 3.24; Cl, 8.21%. Found: C, 69.66; H, 7.38; N, 3.27; Cl, 8.13%.

' EXAMPLE 10 2-Hydroxy-2- [6- (p-methoxybenzoyl) -n-butyl] 5,9-dimethyl-6,7-benzomorphan 26 phenyl) 5",5 ethylenedioxy-n-pentyl]-5,9-dimethyl- 6,7-benzomorphan, m.p.: 177 C.

meg-g 2600, 1620, 1597, 1574, 1497, 1179, 1038, 978,850,808

Anal.-Calcd. for C2gH37N04: C, 74.47; H, 18.26; N, 3.10%. Found: C, 74,63; H, 8.10; N, 3.17%.

(b) 2' Hydroxy 2-[6-(p-methoxybenzoyl)-n-butyl]- 5,9-dimethyl -6,7 benzomorphan: Following the procedure of Example 9, but using 2' hydroxy 2-[5"-(pmethoxyphenyl) 5",5" ethylenedioxy-n-pentyl]-5,9-dimethyl-6,7-benzomorphan, there is obtained a crude product which is recrystallized from n-butanol to yield pure 2' hydroxy 2 [6-(p-methoxybenzoyl)-n-butyl]-5,9- dimethyl-6,7-benzomorphan, m.p.: 181-182 C.

m ggg z 2600, 1668, 1592, 1569, 1495, 1169, 1092,

Anal.Calcd. for C H NO C, 76.62; H, 8.61; N, 3.44%. Found: C, 76.19; H, 8.48; N, 3.60%.

EXAMPLE 11 2-Hydroxy-2- [7- 3 ,4-dimethoxybenzoyl -n-propyl] 5,9-dimethyl-6,7-benzomorphan (a) 2' Hydroxy 2 [4" (3,4-dimethoxyphenyl)- 4",4" cthylenedioxy-n-butyl] 5,9 dimethyl 6,7- benzomorphan: According to the procedure of Example 1(a), the reaction of 1.52 g. of 2-hydroxy-5,9-dimethyl- 6,7-benzomorphan with 2.2 g. of 4-(3',4 dimethoxyphenyl)-4,4 ethylenedioxy 1 chlorobutane gives 2'- hydroxy 2 [4" (3,4-dimethoxyphenyl)-4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl 6,7-benzom0rphan, m.p.s 162-l63 C.

Anal.-Calcd. for C H NO C, 71.92; H, 7.98; N, 3.00%. Found: C, 71.96; H, 7.82; N, 2.93%.

(b) 2' Hydroxy 2 -(3,4-dimethoxybenzoyl)-npropyl] 5,9 dimethyl-6,7-benzomorphan: According to the procedure of Example 1(b), 2'-hydroxy-2-[4"-(3,4- dimethoxyphenyl) 4",4" ethylenedioxy-n-butyl]-5,9- dimethyl-6,7-benzomorphan is converted to 2-hydroxy- 2-[ (3,4 dimethoxybenzoyl)-n-propyl]-5,9-dimethyl- 6,7-benzomorphan, m.p.: 156-15 8 C.

IRv 2650, 1660, 1615, 1580, 1510, 1050, 799, 767

Anal.Calcd. for C26H33NO4: c, 73.73; H, 7.85; N. 3.31%. Found: 0, 74.03; H, 8.13;'N, 3.57%.

EXAMPLE l2 2'-Hydroxy-2- ['y- 3-fiuoro-4-methylbenzoyl -n-propyl] 5,9-dimethyl-6,7-benzomorphan EXAMPLE 13 2'-Hy-droxy-2-['y-(p-methylthiobenzoyl)-n-propyl]- 5,9-dirnethy1-6,7-benzomorpha11 Following the procedure of Example 7, but using 4- (p-methylthiophenyl) 4,4-ethylenedioxy-l-chlorobutane, there is obtained a crude product which is recrystallized from ethyl acetate to yield pure 2' hydroxy-2-[ -(p- 27 methylthiobenzoyl)-n-propyl] 5,9 dimethyl-6,7-benzomorphan, m.p.: 154156 C.

IRvgg,-; 2600, 1673, 1615, 1536, 1236, 1090, 302

Anal.Calcd. for C H NO S: C, 73.31; H, 7.63; N. 7.42; S, 7.83%. Found: S, 73.68; H, 7.65; N, 34 7.88%.

EXAMPLE 14 2'-Hydroxy-2- ['y- (o-methoxybenzoyl -n-propyl 5,9-dimethyl- 6,7-benzomorphan Alternatively the 2'-hydroxy-2['y-(o-methoxybenzoyU- n-propyl]-5,9-dimethyl-6,7-benzomorphan is obtained by the procedure of Example 5. m.p.: 132137 C.

Anal.Calcd. for C H NO C, 76.30; H, 7.94; N, 3.56%. Found: C, 76.37; H, 7.82; N, 3.48%.

EXAMPLE 2'-Hydr0xy-2- [v- (o-methoxybenzoyl) -n-propyl] -5- methyl-9-ethyl-6,7-benzomorphan IRv 1610, 1600, 1532, 1500, 752

Anal.Calcd. for C2gH37NO4: C, 74.47; H, 8.26; N, 3.10%. Found: C, 74.37; H, 8.18; N, 3.18%.

(b) 2' Hydroxy-2-['y-(o-methoxybenzoyl)-r1-propyl]- 5-methyl-9-ethyl-6,7-benzomorphan: A mixture of 2.5 g. of 2' hydroxy-2-[4- (o-methoxyphenyl)-4",4"-ethylenedioxy-n-butyl] -5-methyl-9-ethyl 6,7 benzomorphan, ml. of methanol, 10 ml. of water and 1.5 ml. of concentrated hydrochloric acid is refluxed for 1 hour. After the reaction mixture is concentrated under reduced pressure, the mixture is made alkaline with an aqueous ammonia, and is extracted with ether. The ether extracts are Washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness to give the crude compound. Recrystallization from acetone gives 2- hydroxy-2-['y-(o-methoxybenzoyl)-n-propyl] 5 methyl-9-ethyl-6,7-benzomorphan, m.p.: 148-152 C.

rnvg 'g 1670, 1612, 1595, 1573, 759

Anal.Calcd. for C H NO C, 76.62; H, 8.16; N, 3.44%. Found: C, 76.81; H, 8.27; N, 3.43%.

EXAMPLE 16 2-Hydroxy-2- ['y- 2,5 -dimethylbenzoyl) -r1-propyl] -5 methyl-9-ethyl-6,7-benzomorphan (a) 2 Hydroxy-2-[4-(2,5-dimethylphenyl) 4",4- ethylenedioxy-n-butyl] -5-methyl-9-ethyl 6,7 benzomorphan: According to the procedure of Example 1(a), but using 4-(2,5'-dimethylphenyl) 4,4 ethylenedioxy 1- chlorobutane, there is produced 2'-hydroxy-2[4"-(2,5-dimethylphenyl)-4",4"-ethylenedioxy-n-butyl] 5 methyl- 9-ethyl-6,7-benzomorphan, m.p.: 162-164 C.

rnvig -j z 1615, 1530, 1493, 1035, 1060 Anal.Calcd. for C H NO C, 77.46; H, 8.74; N, 3.12%. Found: C, 77.43; H, 8.75; N, 3.10%.

(b) 2' Hydroxy-2- ['y-(2,5-dimethoxybenzoyl)-n-propyl]-5-methyl-9ethyl-6,7-benzomorphan: Following the procedure of Example 1(b), but using 2-hydroxy-2-[4"- (2,5-dimethylphenyl)-4",4"-ethylenedioxy n butyl]-5- methy1-9-ethyl 6,7 benzomorphan, there is obtained a crude product which is recrystallized from acetone to yield pure 2 hydroxy-Z- ['y-(2,5-dimethylbenzoyl)-n-propyl]-5-methyl-9-ethyl 6,7 benzomorphan, m.p.: 152- 155 C.

ravggg z 1690, 1615, 1535, 1495, 1233, 319, 790

Anal.Calcd. for C27H35N'O2: C, 79.96; H, 8.70; N, 3.45%. Found: C, 80.11; H, 8.72; N, 3.42%.

EXAMPLE 17 2'-Hydroxy-2- ['y- (m-nitrobenzoyl) -n-propyl] -5,9- dimethyl 6,7-b enzomorphan.

By subjecting 4-(m-nitrophenyl)4,4-ethylenedioxy 1- chlorobutane to the procedure of Example 7, there is obtained 2-hydroxy-2-[' -(m-nitrobenzoyl)-n-propoy1]-5,9- dimethyl-6,7-benzomorphan, m.p.: 168.5-173 C.

mvgggl 1695, 1610, 1532, 1523, 1345 Anal.Calcd. for C H N O C, 70.56; H, 6.91; N, 6.86%. Found: C, 69.56; H, 6.75; N, 6.33%.

EXAMPLE l8 2'-Hydroxy-2- ('y-benzoyl-n-propyl) -5-methyl- 9-ethyl-6,7-benzomorphan To a mixture of 1.15 g. of 2'-hydroxy-5-methyl-9- ethyl-6,7-benzomorphan, 0.63 g. of sodium bicarbonate and 20 m1. of dimethylformamide is added 1.4 g. of 'ychlorobutyrophenone. The resultant mixture is stirred at 133 C. for 2 hours. The inorganic solid produced is removed by filtration, and the filtrate is concentrated to dryness. The residue is washed with acetone and filtered. The mother liquor is allowed to stand in a refrigerator, and a precipitate is obtained. Recrystallization from ethyl acetate gives 2-hydroxy-2-(' -benzoyl-n-propyl)-5-methy1-9-ethyl 6,7 benzomorphan, m.p.: 168 170 C.

rnvizg gj z 2650, 1633, 1615, 1592, 1575, 921, 356, 792,

Anal.Calcd for C H NO C, 79.53; H, 8.28; N, 3.71%. Found: C, 79.11; H, 8.63; N, 4.14%.

EXAMPLE 19 2'-Hydroxy-2-('y-benzoybn-propyl)-5,9-dimethyl- 6,7-benzomorphan According to the procedure of Example 18, the reaction of 2' hydroxy 5,9-dimethyl-6,7-benzomorphan with 'y chlorobutyrophenon gives 2' hydroxy 2-(7- benzoyl-n-propyl)-5,9-dimethy1-6,7-benzomorphan.

This compound is also prepared according to the procedure of Example 1. m.p.: 172174 C.

Anal.Calcd. for C H NO C, 79.30; H, 8.04; N, 3.85%. Found: C, 79.23; H, 7.85; N, 3.91%.

EXAMPLE 20 B-2'-Hydroxy-2- ['y- (p-fluorobenzoyl) -n-propyl] 5,9-dimethyl-6,7-benzomorphan A mixture of 0.41 g. of 18-2-hydroxy-5,9-dimethyl-6,7- benzomorphan, 0.24 g. of sodium bicarbonate, 0.46 g. of 4 (p fluorophenyl)-4,4-ethylenedioxy-l-chlorobutane and 10 ml. of dimethylformamide is stirred at 110- C. for three hours. This reaction mixture is concentrated under reduced pressure until most of the dimethylformamide has been removed, and water is added thereto and it is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 9 2-hydroxy-2-[4"-(p-fiu0rophenyl) 4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7- benzomorphan as a yellow oil.

1383-": 1603, 1590, 1500, 1220, 1040, 840 To a mixture of 0.78 gof fi' Y .fluorophenyl) 4",4" ethylenedioxy n-butyl]-5,9-dimethyl-6,7-benzomorphan, 5 ml. of methanol and 4 ml. of water is added 0.75 ml. of concentrated hydrochloric acid. The mixture is refluxed for one hour. The reaction mixture is concentrated under reduced pressure to remove the methanol, made alkaline with an aqueous ammonia and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to an amorphous residue. This residue is chromatographed on a silica gel column with ethyl acetate to give the crude product. This compound is recrystallized from ethyl acetate to yield ,6-2-hydroxy- 2 ['y (p fluorobenzoyl)-n-propyl]-5,9-dimethyl-6,7- benzomorphan, m.p.: 133.5 135.0 C.

rRvgg zgg z 1680, 1604, 1592, 1500 Anal.-Calcd. for C H NO F: C, 75.56; H, 7.40; N, 3.67%. Found: C, 75.53; H, 7.35; N, 3.58%.

EXAMPLE 21 fi-2- ['y- (p-Fluorobenzoyl) -n-propyl] 5 ,9-dimethy1- 6,7-benzomorphan A mixture of 0.76 g. of ,8 5,9-dimethyl-6,7-benzomorphan, 0.5 g. of sodium bicarbonate, 0.92 g. of 4-(pfluorophenyl) 4,4-ethylenedioxy-l-chlorobutane and ml. of dimethylformamide is stirred at 130150 C. for 3.5 hours. The solvent is removed under reduced pressure to a residue, to which is added water. The mixture is extracted with ether. The ether extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to give 5 2-[4"-(p-fluorophenyl)-4",4-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7-benzomorphan.

m g-"z 1600, 1502, 1220, 1040 A mixture of 1.3 g. of 13-2- [4-(p-fluorophenyl)-4,4- ethylenedioxy n-butyl]-5,9-dimcthyl-6,7-benzomorphan, 15 ml. of methanol, 10 ml. of water and 2 ml. of concentrated hydrochloric acid is refluxed for one hour, and treated with charcoal and filtered. After the filtrate is concentrated under reduced pressure, it is made alkaline with an aqueous ammonia and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to a residue. This residue is chromatographed on a silica gel column with chloroform to give the product. This base is converted to the hydrochloride by contacting with .dry gaseous hydrogen chloride. This hydrochloride is re- .crystallized from acetone-ethyl acetate to yield fl-2-['y-(pfiuorobenzoyl) n propyl]-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p.: 209.5 210.5 C.

11883; 2400 (broad), 1690, 1595, 1228, 1210, 1158,

- Anal.Calcd. for C H NOFCI: C, 71.71; H, 7.27; N, 3.48%. Found: C, 71.94; H, 7.28; N, 3.22%.

EXAMPLE 22 a-2'Hydroxy-2- ['y- (m-fluorobenzoyl) n-propyl] 5 ,9-dimethyl-6,7-benzomorphan (a) a 2 Hydroxy-2-[4"-(m-fluorophenyl)-4",4"- ethylenedioxy n-butyl]-5,9-dimethyl-6,7-benzomorphan: According to the procedure of Example 1(a), but using 1.15 g. of a-2-hydroxy5,9-dimethyl-6,7-benzomorphan,

30 0.7 g. of sodium bicarbonate, 1.4 g. of 4 (m-fluorophenyl)-4,4-ethylenedioxy-l-chlorobutane and 10 ml. of dimethylformamide, there is produced a 2'-hydroxy-2- [4" (m-fluorophenyl)-4",4"-ethylenedioxy-n-butyl]-5,9- dimethyl-6,7-benzomorphan, m.p.: 172-l81 C.

mug-g 1610, 1585, 1578 Anal.Calcd. for C H NO F: C, 75.56; H, 7.40; N, 3,67%. Found: C, 75.02; H, 7.97; N, 3.85%.

EXAMPLE 23 a2-Hydroxy-2-[' -(rn-trifiuoromethylbenzoyl)-npropyl] -5,9-dimethyl-6,7-benzomorphan Following the procedure of Example 7, but using 4- (m-trifluoromethylphenyl) 4,4 ethylenedioxy-l-chlorobutane, there is obtained a crude product which is recrystallized from ethyl acetate-isopropyl ether to yield pure a-2-hydroxy 2 -(m-trifluoromethylbenzoyl)- n-propyl] 5,9 dimethyl 6,7 benzomorphan, m.p.: 137-139 C.

Anal.Calcd. for C H NO F C, 69.59; H, 6.54; N, 3.25%. Found: C, 69.59; H, 6.48; N, 3.24%.

EXAMPLE 24 a-2'-Methoxy-2- ['y- (p-fluorobenzoyl) -n-propyl] 5 ,9-dimethyl-6,7-benzomorphan According to the procedure of Example 23, the reaction of a-2'-methoxy 5,9 -dirnethyl 6,7 benzomorphan (2.31 g.) with 2.7 g. of 4- (p-fiuorophenyl) 4,4 ethylenedioxy 1 chlorobutane gives a-2-methoxy-2-[*y-(p-fiuorO- benzoyl)-n-propyl] 5,9 dimethyl 6,7 benzomorphan hydrochloride, m.p.: 144-152 C. (hygroscopic prism).

3400, (broad), 2500 (broad), 1690, 1610, 1595 EXAMPLE 25 2-Hydroxy-2- ['y- (p-fiuorob enzoyl) -n-propyl] -5- methyl-6,7-benzomorphan (a) 2-Hydroxy 2 [4"- (p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl] 5 methyl 6,7 benzomorphan: A mixture of 0.8 g. of 2'-hydroxy 5 methyl-6,7-benzomorphan, 0.5 g. of sodium bicarbonate, 1.06 g. of 4-(pfluorophenyl) 4,4 ethylenedioxy 1 chlorobutane and 15 ml. of dimethylformamide is stirred at 155 C. for 3.5 hours. The precipitate produced is filtered off. The filtrate is concentrated under reduced pressure to remove the dimethylformamide, and water is added thereto and it is extracted with ether. The extracts are washed, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to dryness to give 2'-hydroxy-2- [4"-(p-fluorophenyl) 4",4" ethylenedioxy-n-butyl]-5- methyl-6,7-benzomorphan, as a viscous liquid.

IRv 1600, 1580, 1505, 1220, 1155, 1040, 840

(b) 2-Hydroxy 2 ['y-(p-fluorobenzoyl)-n-propyl]- S-methyl 6,7 benzomorphan: A mixture of 1.7 g. of 2'-hydroxy 2 [4"-(p-fluorophenyl) 4,4"-ethylenedioxy n butyl] 5 methyl 6,7 benzomorphan, 8 ml. of methanol, 4 ml. of Water and 0.8 ml. of methanol, 4 ml. of water and 0.8 ml. of concentrated cm: IRV m 31 hydrochloric acid is stirred at 79 -81 C. for one hour, and treated with 0.05 g. of decolorizing charcoal and filtered. After the filtrate is concentrated under reduced pressure to remove the methanol, it is made alkaline with an aqueous ammonia and extracted with ether. The extracts are concentrated to dryness to give the crude product, which is recrystallized from acetone to yield 2'-hydroxy 2 ['y-(p-fluorobenzoyl)-n-propyl]-5-methyl-6,7- benzomorphan, m.p.: 1695-1715 C.

ems-

Anal.Calcd. for C H NO F: C, 75.17; H, 7.13; N, 3.81%. Found: C, 74.93; H, 7.15; N; 3.77%.

EXAMPLE 26 2- ['y- (p-Fluorobenzoyl) -n-propyl] --methyl-6,7- benzomorphan (a) 2-[4"-(p-Fluorophenyl) 4",4" ethylenedioxy-nbutyl] 5 methyl 6,7 benzomorphan: A mixture of 1.87 g. of 5-methyl-6,7-benzomorphan, 1.0 g. of sodium bicarbonate, 2.45 g. of 4-(p-fluorophenyl) 4,4 ethylenedioxy 1 chlorobutane and 20 ml. of dimethylformamide is stirred at 110-145 C. for 4 hours. This mixture is concentrated under reduced pressure until most of the dimethylformamide has been removed, and water is added thereto. The mixture is extracted several times with benzene. The extracts are washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 2-[4"-(pfiuorophenyl) 4",4" ethylenedioxy-n-butyl]-5-methyl- 6,7-benzomorphan.

mug-51,: 1000, 1502, 1220, 1153, 1040, 340, 700, 680

(b) 2-[' -(p-Fluorobenzoyl)-n-propyl] 5 methyl-6,7- benzomorphan: To a mixture of 3.6 g. of 2- [4"-(p-fiuorophenyl) 4",4" ethylenedioxy-n-butyl] 5 methyl-6,7- benzomorphan, 40 ml. of methanol and ml. of water is added 5 ml. of concentrated hydrochloric acid. After the resultant mixture is refluxed for 1 hour, it is treated with charcoal and filtered. The filtrate is concentrated under reduced pressure to residue, which is made alkaline with an aqueous ammonia and extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to a residue, which is distilled under reduced pressure to yield 2-[y-(p-fiuorobenzoyl)-n-propyl] 5 methyl-6,7- benzomorphan, b.p.: 170198 C./0.3 mm. Hg.

iainln- 1 78 1592, 1230, 1156, 837, 760

This free base is converted to the hydrochloride by contacting with dry gaseous hydrogen chloride. Recrystallization from acetone-methanol gives 2-['y-(p-fiuorobenzoyl)- n-propyl] 5 methyl 6,7 benzomorphan hydrochloride, m.p.: 2l9220 C.

Anal.Calcd. for C H NOFCl: C, 71.21; H, 7.01; N, 3.61%. Found: C, 71.20; H, 6.98; N, 3.51%.

EXAMPLE 27 2-(' -Benzoyl-n-propyl)-5-methyl-6,7-benzomorphan To a mixture of 0.47 g. of S-methyl-6,7-benzomorphan,

0.3 g. of sodium bicarbonate and 10 m1. of dimethyl- 1111 2500 (broad), 1685, 1593, 1530, 1212 EXAMPLE 28 2-Hydroxy-2- ['y- (p-fluorobenzoyl) -n-propyl] -6,7- benzomorphan (a) 2-Hydroxy 2 [4" (p fluorophenyl)-4",4"- ethylenedioxy n butyl] 6,7 benzomorphan: To a mixture of 0.45 g. of 2' hydroxy 6,7 benzomorphan, 0.3 g. of sodium bicarbonate and 10 ml. of dimethylformamide is added 0.64 g. of 4 (p-fluorophenyl) 4,4 ethylenedioxy-l-bromobutane. The resultant mixture is stirred at 130-150 C. for 3.5 hours. After the precipitate produced is filtered off, the filtrate is concentrated to remove the dimethylformamide and water is added thereto. The mixture is extracted with ether. The ether extracts are concentrated to dryness to yield 2'-hydroxy-2-[4"-(p-fluorophenyl) 4",4 ethylenedioxy n butyl]-6,7-benzomorphan as an oil.

IRvffi fit 1600, 1505, 1225, 1160, 1050, 840

(b) 2 Hydroxy 2 ['y-(p-fluorobenzoyl)-n-propyl]- 6,7-benzomorphan: A mixture of 1.05 g. of 2'-hydroxy-2- [4-(p-fluorophenyl) 4",4" ethylenedioxy-n-butyl]-6,7- benzomorphan, 5 m1. of methanol, 2.5 ml. of water and 0.5 ml. of concentrated hydrochloric acid is stirred at 82- 97 C. for one hour, and is treated with 0.03 g. of charcoal and filtered. After the filtrate is concentrated to remove the methanol, it is made alkaline with an aqueous ammonia and extracted with ether. The ether extract is concentrated to a residue, which is crystallized from acetone. Recrystallization from acetone gives 2'-hydroxy-2- -(p-fluorobenzoyl) n propyl] 6,7 benzomorphan, m.p.: 165.5-169.5 C.

Anal.Calcd. for C H NO F: C, 74.76; H, 6.84; N, 3.96%. Found: C, 75.08; H, 6.64; N, 4.09%.

EXAMPLE 29 2- ['y- (p-Fluorob enzoyl) -n-propyl] -6.7-b enzomorphan (a) 2 [4" (p-Fluorophenyl)-4", "-ethylenedioxy-nbutyl]-6,7-benzomorphan: A mixture of 1.7 g. of 6,7-benzomorphan, 2.5 g. of 4-(p-fluorophenyl)-4,4-ethylenedioxy-l-chlorobutane, 1.01 g. of sodium bicarbonate and 20 m1. of dimethylformamide is stirred at -155 C. for 3.5 hours. The mixture is concentrated under reduced pressure until most of the solvent has been removed, and water is added thereto. The mixture is extracted several times with ether. The combined extracts are Washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to give 2 [4" (p fluorophenyl)-4",4"-ethylenedioxy-nbuty1]-6,7-benzomorphan as a liquid. n 1.5459.

(b) 2 ['y (p Fluorobenzoyl)-n-propyl]-6,7-benzo-' morphan: To a mixture of 3.5 g. of 2-[4"-(p-fluorophenyl) 4",4" ethylenedioxy n butyl]-6,7-benzomorphan, 50 m1. of methanol and 15 ml. of water is added 5 ml. of concentrated hydrochloric acid. After the resultant mixture is refluxed for one hour, the mixture is concentrated under reduced pressure to residue, which is made alkaline with an aqueous ammonia and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to a residue, which is converted to the hydrochloride to give 2 ['y (p fluorobenzoy1)-n-propyl]- 33 6,7-benzomorphan hydrochloride, m.p.: 209-211 C. (methanol-acetone) Anal.-Calcd. for C H NOFCI: C, 70.67; H, 6.74; N, 3.74%. Found: C, 71.00; H, 6.97; N, 3.83%.

EXAMPLE 30 2-[7-(p-Methoxybenzoyl)-n-propyl]-6,7-benzomorphan (a) 2 [4" (p Methoxyphenyl) 4",4 ethylenedioxy-n-butyl]-6,7-benzomorphan: According to the procedure of Example 28(a), the reaction of 1.62 g. of 6,7- benzomorphan with 2.4 g. of 4 (p methoxyphenyl)-4,4- ethylenedioxy-l-chlorobutane gives 2 [4-(pmethoxyphenyl) 4",4" ethylenedioxy n butyl]-6,7-benzmorphan as a liquid. 71 1.5600.

(b) 2 ['y (p Methoxybenzoyl) n propyl]-6,7- benzomorphan: According to the procedure of Example 28(b), 2 [4" (p methoxyphenyl) 4",4" ethylenedioxy n butyl] 6,7 benzomorphan converts to 2- ['y- (p methoxybenzoyl) n propyl] 6,7 benzomorphan hydrochloride, m.p.: 211.5 2l3 C. (acetone-methanol).

AnaL-Calcd. for C H NO Cl: C, 71.58; H, 7.31; N, 3.63%. Found: C, 71.65; H, 7.45; N, 3.58%.

EXAMPLE 3 1 a-2'-Nitl'O-2- [v-(p-fluorobenzoyl) -n-propyl] 5,9-dimethyl-6,7-benzomorphan A mixture of 2.46 g. of 01-2'-nitro-5,9-dimethyl-6,7-ben- 'zomorphan, 20 ml. of dimethylformamide, 1.26 g. of sodium bicarbonate and 2.7 g. of 4-(p-fluorophenyl)-4,4- ethylenedioxy-l-chlorobutane is stirred at 130-l50 C. for 3.5 hours. The mixture is concentrated under reduced pressure until the dimethylformamide has been removed, and water is added thereto and it is extracted with ether. The extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to dryness. The residue obtained is used without purification. To a mixture of 4.8 g. of crude a-2'-11itIO-2- [4- (p-fluorophenyl) -4",4"-ethylenedioxy-n-butyl]-5,9-dimethyl-6,7-benzomorphan, 25 ml. of methanol and 12 ml. of Water is added 6 ml. of concentrated hydrochloric acid. The mixture is boiled for one hour, treated with decolorizing charcoal and filtered. After the filtrate is concentrated under reduced pressure, it is made alkaline with an aqueous ammonia and extracted with ether. The extract is Washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to a residue. This residue is converted to the hydrochloride. Recrystallization from acetone-methanol gives a-2'-flitl0- 2- (p-fiuorobenzoyl)-n-propyl]-5,9-dimethyl 6,7 benzomorphan hydrochloride, m.p.: 222-223 C. (decomp).

mpg-,5 2400, 1680, 1520, 134.0, 1230, 1160, 840, 820,

Anal.CalCd. for C24H23N203Fc1: C, H, N, 6.27%. Found: C, 65.22; H, 6.52; N, 6.10%.

EXAMPLE 32 a-2'-Hydroxy-2- ['y- (p-fluorobenzoyl) -n-propyl] ,8,9=trimethyl-6,7-benzomorphan (a) a-2'-Hydroxy 2 [4"- (p-fiuorophenyl)-4",4"-ethylenedioxy-n-butyl]-5,8,9-trimethyl-6,7-benzomorphan: A mixture of 0.6 g. of a-2'-hydroxy-5,8,9-trimethyl-6,7-benzomorphan, 0.26 g. of sodium bicarbonate, 0.64 g. of 4- (p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane and 10 ml. of dimethylformamide is stirred at 130-145 C. for 4 hours. The solvent is removed under reduced pressure to a residue, to which is added water. The mixture is extracted with ether. The extract is washed, dried and filtered. The filtrate is concentrated to give d-2'-hydroxy-2- [4"- (p-fluorophenyl)-4",4 ethylenedioxy n butyl]- 5,8,9-trimethyl-6,7-benzomorphan as an oil.

(b) a-2-Hydroxy-2-['y-(p-fluorobenzoyl) n propyl]- 5,8,9-trimethyl-6,7-benzomorphan: To a mixture of 1.2 g. of u-2'-hydroxy-2-[4"-(p-fluorophenyl-4,4-ethylenedioxy-n-butyl]-5,8,9-trimethyl-6,7-benzomorphan, 15 ml. of methanol and 6 ml. of Water is added 2 ml. of concentrated hydrochloric acid. After the resultant mixture is refluxed for 1 hour, it is concentrated under reduced pressure to a residue, which is made alkaline with excess aqueous ammonia and extracted with chloroform. The organic solution is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to an amorphous residue. This residue is chromatographed on a silica gel column and on an aluminum oxide column with chloroform and ethyl acetate to give the crude product. This compound is recrystallized from ethyl acetate to yield ot-2'-hydroxy-2- [7- (p-fluorobenzoyl)- n propyl] 5,8,9 trimethyl 6,7 benzomorphan, m.p.: 144.5146 C.

Anal.Calcd. for C H NO F: C, 75.92; H, 7.65; N, 3.54%. Found: C, 76.11; H, 7.56; N, 3.45%.

EXAMPLE 33 u-2'-Hydroxy-2- B (p-fluorob enzoyl) ethyl] 5,9-dimethyl-6,7-benzomorphan To a solution of 4.0 'g. of a-2'-hydroxy-5,9-dimethyl- 6,7-benzomorphan in 45 ml. of dimethylformamide are added 2.32 g. of sodium bicarbonate and a solution of 4.67 g. of 3-(p-fiuorophenyl)-3,3-ethylenedioxy-1-chloropropane in 20 ml. of dimethylformamide with stirring. The resultant mixture is refluxed for 7 hours and the precipitate formed is filtered off. The filtrate is concentrated to dryness to give u-2'-hydroxy-2-[3"-(p-fiuorophenyl)-3",3" ethylenedioxy n propyl] -5,9-dimethyl- 6,7-benzomorphan, as a brown oil.

A mixture of 8.5 g. of u-2'-hydroxy-2-[3"-(p-fiuorophenyl)-3",3" ethylenedioxy n propyl] 5,9-dimethy1- 6,7-benz0morphan, ml. of methanol, 40 ml. of water and 15 ml. of concentrated hydrochloric acid is refluxed for one hour. The reaction mixture is concentrated under reduced pressure to remove the methanol and made alkaline with an aqueous ammonia. The solution is extracted with ether. The ether extracts are washed, dried and filtered. The solvent is removed to give the crude oil, to which are added ether and ethyl acetate. The mixture is allowed to stand in a refrigerator, and a precipitate is obtained. Recrystallization from ethyl acetate gives (2'2 hydroxy-2-[B-(p fiuorobenzoyDethyl]-5,9-dimethyl-6,7- benzomorphan, m.p.: 156.5 l60 C.

Anal.Calcd. for C23H26NO2F: c, 75.18; H, 7.13; N, 3.81%. Found: c, 74.29; H, 7.36; N, 3.38%.

EXAMPLE 34 2 '-Hydroxy-2- [flp-fluorobenzoyl) ethyl] -6,7- benzomorphan According to the procedure of Example 33, but using 3-(p-fluorophenyl)-3,3-ethylenedioxy 1 chloropropane, there is produced 2-hydroxy 2 [B-(p-fluorobenzoyl) ethyl]-6,7-benzomorphan, m.p.: -159 C.

IRvi,;; 2675, 2590, 1685, 1618, 1596, 1498 Anal.Calcd. for C H NO F: C, 74.13; H, 6.53; N, 4.13%. Found: C, 75.00; H, 7.05; N, 4.54%.

35 EXAMPLE 35 a-'2'-Hydroxy-2- S-benzoylethyl) ,9-dimethy1- 6,7-benzomorphan AnaL-Calcd. for C H NO C, 79.05; H, 7.79; N, 4.01%. Found: C, 79.04; H, 7.92; N, 4.55%.

EXAMPLE 36 2- 8- (p-Fluorobenzoyl) ethyl] -5-methyl6,7-

, benzornorphan (a) 2-[3"-(pJFluorophenyl) 3",3" ethylenedioxy-npropyl] 5 methyl 6,7 benzornorphan: Following the procedure of Example 26(a), but using 3-(p-fluorophenyl)-3,3-ethylenedioxy-l-chloropropane, there is obtained 2-[3-(p-fluoropheny1) 3",3" ethylenedioxy-npropyl] 5 methyl 6,7 benzornorphan, as a viscous liquid.

, (b) 2-[,B-(p-Fluorobenzoyl)ethyl]-5-methyl-6,7-benzomorphan: According to the procedure of Example 26(b), but using 2-[3"-(p-fiuorophenyl)-3", "-ethylenedioxy-npropyl] 5 methyl 6,7 benzornorphan, there is produced 2 [,6-(p-fluorobenzoyl)ethyl]-5-methyl- 6,7-benzomorphan hydrochloride, m.p.: 177 -178 C.

Ana1.Calcd. for C H NOClF: C, 70.67; H, 6.74; N, 3.75; CI, 9.48%. Found: C, 70.72; H, 6.67; N, 3.80; CI, 9.86%.

EXAMPLE 37 61-2 '-Hydroxy-2- [fl- (p-methoxybenzoyl) ethyl] -5 9- dimethyl-6,7-benzomorphan (a) u-2-Hydroxy-2-[3 (p-methoxyphenyl) 3",3"- ethylenedioxy n propyl] 5,9 dimethyl 6,7- benzomorphan: According to the procedure of Example 25(a), the reaction of 2.17 g. of a-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan with 2.67 g. of 3-(p-methoxyphenyl)-3,3-ethylenedioxy 1 chloropropane gives (1'2 hydroxy 2-[3"-(p-methoxyphenyl)-3",3"-ethylenedioxyn-propyl]-5,9-dimethyl-6,7-benzomorphan, m.p.: 165 169 C.

mug-2, 2600, 1603, 1578, 1180, 795

(b) u-2-Hydroxy 2 [/3 (p methoxybenzoyl)ethyl- 5,9-dimethyl-6,7-benzomorphan: According to the procedure of Example 25(b), oz-2-hydroxy-2-[3"-(p-methoxyphenyl)-3",3"-ethylenedioxy n propyl]-5,9-dimethyl- 6,7-benzornorphan converts to u-2-hydroxy 2 S-(pmethoxybenzoyl)ethyl] 5,9-dimethyl-6,7-benzomorphan, m.p.: 172175 C. (methanol-ethyl acetate).

muggy-g 2650, 1674, 1607, 1580, 1501, 1182, 796

'Anal.-Calcd. for C24H27NO3Z C, 75.96; H, 7.70; N, 3.69%. Found: C, 75.71; H, 7.72; N, 3.73%.

36 EXAMPLE 3s u-2-Hydroxy- 2- [6- (p-fluorob enzoyl) -n-propyl -3 ,5,9- trirnethyl-6,7-benzomorphan (a) a 2' Hydroxy 2 [4" (p fluorophenyl)- 4",4" ethylenedioxy n butyl] 3',5,9 trimethyl-6,7- benzomorphan: To a mixture of 1.0 g. of a-2-hydroxy- 3,5,9-trimethyl-6,7-benzomorphan, 0.58 g. of sodium bicarbonate and 10 ml. of dimethylformamide is added 1.27 g. of 4- (p-fluorophenyl)-4,4-ethylenedioxy-l-chlorobutane. The mixture is stirred at 145 C. for 4 hours and the precipitate formed is filtered off. The filtrate is concentrated to remove the dimethylformamide, and water is added thereto and it is extracted with ether. The extract is Washed, dried and filtered. The solvent is removed to give the crude product. Recrystallization from methanol gives a-2'-hydroxy-2- [4"- (p-fiuorophenyl) -4,4"-ethylenedioxy-n-butyl]-3',5,9-trimethyl-6,7 benzornorphan, m.p.: 166168 C.

mvgig j 2650, 1615, 1600, 1504, 1045, 957, 850

Anal.Calcd. for C H NO F: C, 73.77; H, 7.80; N, 3.19%. Found: C, 73.44; H, 7.63; N, 3.03%.

(b) a 2' Hydroxy-2-['y-(p-fluorobenzoyl)-n-propyl]- 3,5,9-trimethyl-6,7-benzomorphan: A mixture of 0.9 g. of a-2-hydroxy-2-[4" (p-fiuorophenyl) 4,4"-ethylenedioxy-n-butyl] 3',5,9 trimethyl-6,7-benzomorphan, 20 ml. of methanol, 10 ml. of water and 1.5 ml. of concentrated hydrochloric acid is refluxed for 1 hour, treated with decolorizing charcoal and concentrated under reduced pressure to remove the methanol. The residual solution is made alkaline with an aqueous ammonia and extracted with ether. The extract is washed, dried, filtered and concentrated to dryness. This free base is converted to hydrochloride and recrystallization from methanolacetone gives oz 2' hydroxy-Z-['y-(p-fluorobenzoyD-npropyl] 3' 5,9 trimethyl 6,7 benzornorphan hydrochloride, m.p.: 214-217 C.

mpg-gi 5150, 2600, 1675, 1610, 1590, 1500, 1025, 833

Anal.Calcd. for C H NO FCl: C, 69.51; H, 7.23; N, 3.24; Cl, 8.21%. Found: C, 69.38; H, 7.35; N, 3.10; CI. 8.01%.

'EXAMPLE 39 6-2'-Hydroxy-2- 6- (p-methoxyb enzoyl) -n-butyl] 3'-5,9-trimethyl-6,7-benzomorphan (a) a 2' Hydroxy-2[5-(p-methoxyphenyl)-5",5"- ethylenedioxy-n-pentyl] 3' 5,9 trimethyl-6,7-benzomorphan: According to the procedure of Example 38(a), the reaction of 1.15 g. of a-2'-hydroxy-3'-5,9-trimethyl- 6,7-benzomorphan with 1.5 "5'61 5-(p-methoxyphenyl)- 5,5 ethylenedioxy-1-chloropentane gives a-2'-hydroxy-2- [5"-(p-methoxyphenyl) 5",5"-ethylenedioxy-n-pentyl]- 3,5,9-trimethyl-6,7-benzomorphan.

(b) o: 2-Hydroxy-2-[6-(p-methoxybenzoyl)-n-butyl]- 3,5,9 trimethyl-6,7-benzomorphan: According to the procedure of Example 38(b), a-2' hydroxy-2-[5"-(pmethoxyphenyl) 5",5" ethylenedioxy-n-pentyl]-3,5,9- trimethyl-6,7-benzomorphan converts to u-2'-hydroxy-2- [B-(p methoxybenzoyl)-n-butyl] 3,5,9 trimethyl-6,7- benzomorphan, m.p.: 128 -130 C.

invggf 2650, 1668, 1600, 1570, 842, 760

Anal.--Calcd. for C2'1H35NO3I C, 76.92; H, 8.37; N, 3.32%. Found: C, 76.47; H, 7.94; N, 3.26%.

EXAMPLE 40 u-2'-Acetoxy-2- ['y- (p-fiuorobenzoyl) -n-propyl] 5,9-

dimethyl-6,7-benzomorphan A mixture of 3.82 g. of a-2' hydroxy-Z- -(p-fluorobenz0y1)-n propyl] 5,9 dimethyl-6,7-benzomorphan and 20 ml. of acetic anhydride is stirred at 96-97.5 C. for one hour, cooled and poured into ice water. The resultant mixture is made alkaline with aqueous potassium hydroxide (50%) while keeping ice cold, and the liberated base is shaken quickly into ether. The ether extract is washed, dried and filtered. The filtrate is evaporated and allowed to stand in the refrigerator. The precipitate obtained is collected and recrystallized from acetone-ether to yield ot-2 acetoxy-2-['y-(p-fluorobenzoyl)-n-propyl]- 5,9-dimethyl 6,7 benzomorphan acetate, m.p.: 188- 189.5 C.

EXAMPLE 41 Step 1: {3-2'-Nitro-2,5,9-trimethyl-6,7-benzornorphan ,8-2,5,9-Trimethyl-6,7-benzomorphan (6.5 g.) in glacial acetic acid (14 ml.) is added dropwise to an ice-cold mixture of fuming HNO (34 ml.) and glacial acetic acid (21 ml.). The mixture is stirred overnight at 25 (3., and the solvent is removed in vacuo.

Ice, water and NH OH are added to the oily residue, and crystals produced are then recrystallized from methanol to give fl-2'-nitro-2,5,9-trimethyl-6,7-benzomorphan, m.p.: 141.5 142.5 C.

The basic solution is extracted with ether, and the product obtained from the ether extract is recrystallized from methanol to give fi-1'-nitro or 78-4 nitro 2,5,9- trimethyl-6,7 benzomorphan, m.p.: 121122 C. besides ,B-2'-nitro-2.,5,9-trimethyl-6,7-benzomorphan.

Anal.-Calcd. for ,8-2' nitro 2,5,9 trimethyl-6,7-

benzomorphan (C H N O C, 69.20; H, 7.74; N,

10.76%. Found: C, 69.29; H, 7.88; N, 10.91%.

Anal.--Calcd. for [3-1'- or 4'-nitro-2,5,9-trimethyl-6,7- benzomorphan (C H N O C, 69.20; H, 7.74; N, 10.76%. Found: C, 69.12; H, 7.83; N, 10.66%.

Step 2: ,8-2'-Amino-2,5,9-trimethyl-6,7-benzomorphan Zinc powder (30 g.) is added dropwise to a mixture of B-2'-nitro-2,5,9-trimethyl-6,7-benzomorphan (4.1 g.), concentrated hydrochloric acid (100 ml.) and water (50 The mixture is stirred for 1.5 hours at 90-l00 C. and NH OH is added to this mixture.

The basic solution is extracted with chloroform.

The extract is dried (MgSO and filtered, and the solvent is removed in vacuo to give 3.6 g. of an oily residue.

The product is converted to the hydrochloride salt which is recrystallized from a mixture of acetone and methanol to give 18 2 amino-2,5,9-trimethyl-6,7-benzomorphan, m.p.: 278-282 C. (decomp.).

Step 3: fl-2'-Hydroxy-2,5,9-trimethy1-6,7-benzomorphan To ,3 2' amino 2,5,9-trimethyl-6,7-benzomorphan (3.35 g.) in 30 ml. of 3N sulfuric acid is adde stirring) during 20 min. 1.21 g. of sodium nitrite in ml. of water. The solution is then treated at 70 C. with a solution of ml. of water and 20 ml. of sulfuric acid, warmed at 80 C. in 30 min., poured into ice-water. NH OH is added to this solution and extracted with chloroform. The dried extract is evaporated to give 3.65 g. of a red-brown residue which is crystallized from ether and then recrystallized from acetone to give ;8-2'-hydroxy- 2,5,9 trimethyl 6,7-benzomorphan, m.p.: 202208 C.

wherein R is a hydrogen atom, a C C alkoxy group, an acetoxy group, a hydroxyl group, a nitro group, a halogen atom, a cyano group, an amino group, a carboxyl group, a carbamoyl group or a sulfo group; R is a hydrogen atom, a C C alkyl group or a group of the formula, (CmH )(R (wherein m is an integer of 1-6; p is an integer of 1-2; and R is a hydroxyl group or a 0-0 alkoxy group); R is a hydrogen atom or a C -C alkyl group; R and R are independently a hydrogen atom, a halogen atom, a C -C alkyl group, a (I -C alkoxy group, a C C alkylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxyl group, or R and R may from a C -C alkylidene group hydrogen atom or a C -C alkyl group; R is a hydrogen atom, a C C alkyl group, a phenyl group or a 0-0 alkoxyphenyl group; R is a hydrogen atom or a hydroxyl group, or R and R may form a C --C alkylidene group or a carbonyl group together with a carbon atom to which these substituents are bonded; and n is an integer of 24, provided that, when n is an integer of 2; R and R are methyl groups; R is a hydrogen atom or a hydroxyl group; and R R R R and R are hydrogen atoms, R, must be a halogen atom, C -C alkyl group, a C C alkoxy group, a C -C alkylthio group, a nitro group, a trifluoromethyl group, an amino group or a hydroxyl group.

2. A benzomorphan derivative of the formula:

wherein R is a hydrogen atom, a hydroxyl group or a C C alkoxy group; R and R are independently 0-0 alkyl groups; n is an integer of 3 or 4; and R and R are as defined in Claim 1.

3. 2' Hydroxy 2- ['y-(p-fiuorobenzoyl)-n-propyl] -5,9- dlmethyl-6,7-benzomorphan.

4. 2' Hydroxy 2 ['y-(p-fluorobenzoyl)-n-propyl]-5- methyl-9-ethyl-6,7-benzomorphan.

5. 2' Hydroxy-2-['y-(p-methoxybenzoyl)-n-propyl]-5- methyl-9-ethyl-6,7-benzomorphan.

6. 2' Hydroxy 2 ['1 (3,4 dimethoxybenzoyl) npropyl] -5 ,9-d1methyl-6,7-benzomorphan.

7. 2 ['Y (P Fluorobenzoyl)-npropyl]-5,9-dimethyl- 6,7-benzomorphan.

8. 2' Hydroxy 2-['y-(p-methoxybenzoyD-nr0 1 5,9-dimethyl-6,7-benzomorphan. P py 9. 2' Hydroxy 2-('y-benzoyl-n-propyl) -5,9'-dimethyl- 6,7-benzomorphan.

10. 2' Hydroxy 2-(v-benzoyl-n-propyl) -5-methyl-9- ethyl-6,7-benzomorphan.

11. 2' Methoxy-Z- ['y-(p-fluorobenzoyl)'-n-propyl]-5,9- dimethyl-6,7-benzomorphan.

dimethyl-6,7-benzornorphan.

39 13. 2-Hydroxy 2 ['y-(m-fluorobenzoyl)-npropyl]- 5,9-dimethyl-6,7-benzomorphan.

14. A benzomorphan derivative of the formula:

Qr r

wherein R is a hydrogen atom, a hydroxyl group, an acetoxy group or a C C alkoxy group; R is a C -C alkyl group; n is an integer of 3 or 4; and R and R are as defined in Claim 1.

15. 2'-Hydroxy 2 ['Y-(P-fluorobenzoyl)-n-propyl]- 5methyl-6,7-benzomorphan.

16. 2-( -Benzoyl-n-propyl) 5 methyl 6,7 benzomorphan.

17. 2-[ -(p-Fluorobenzoyl)-n-propyl] 5 methyl-6,7- benzomorphan.

18. 2' HydroXy-2-['y-(p-methoxybenzoyl)-n-propyl]- 5-methyl-6,7-benzomorphan.

19. 2' Hydroxy-Z-('ybenzoyl-n-propy1) 5 methyl- 6,7-benzomorphan.

20. A benzomorphan derivative of the formula:

wherein R is a hydrogen atom, a hydroxyl group, an acetoxy group or a C C alkoxy group; n is an integer of 3 or 4; and R and R are as defined in Claim 1..

21. 2-Hydroxy 2 ['y-(pfluorobenzoyl)-n-propyl]- 6,7-benzomorphan.

22. 2- ['y- (p-Fluorobenzoyl)-n-propyl] 6,7 benzomorphan.

23. 2' Hydroxy-2- ['y-(p-methoxybenzoyl)-n-propyl]- 6,7-benzomorphan.

24. 2-Hydroxy 2 ('y-benzoyl-n-propyl)6,7-beuzomorphan.

25. A benzomorphan derivative of the formula:

wherein R is a hydrogen atom, a hydroxyl group or a C C alkoxy group; R is a hydrogen atom or a C C alkyl group; n is an integer of 3 or 4; and R R k m and p are as defined in Claim 1.

26. A benzomorphan derivative of the formula:

N R MN R 1%.

wherein R is a halogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, a carbamoyl group or a sulfo group; R and R are hydrogen atoms or C -C alkyl groups; and R R and n are as defined in Claim 1.

27. A benzomorphan derivative of the formula:

wherein R is a hydrogen atom, a hydroxyl group or a C C alkoxy group; R and R are hydrogen atoms or C C alkyl groups; and R R R R R and n are as defined in Claim 1, provided that when R and R are hydrogen atoms, R must be a C -C alkyl group.

28. 2'-Hydroxy 2 ['Y-(P-fluorobenzoyl)-n-propyl]- 5,8,9-trimethyl-6,7-benzomorphan.

29. A benzomorphan derivative of the formula:

I it

wherein R is a hydrogen atom, a hydroxyl group, an acetoxy group or a C -C alkoxy group; R is a C -C alkyl group; n is an integer of 3 or 4; and R and R are as defined in Claim 1.

30. 2'-Hydroxy 2 ['y-(p-flllorobenzoyl)-n-propy1]- 9-methyl-6,7-benzomorphan.

31. 2' Hydroxy-Z-[ -(p-methoxybenzoyl)-n-propyl]- 9-methyl-6,7-benzomorphan.

32. 2' Hydroxy-Z-(' -benzoyl-mpropyl)-9-methyl-6,7- benzomorphan.

33. 2 ['y-(p-Fluorobenzoyl)-n-propyl]-9-methyl-6,7- benzomorphan.

34. A benzomorphan derivative of the formula:

I I R1

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3932422 *May 20, 1974Jan 13, 1976Sterling Drug Inc.8-Methylene-3-azabicyclo[3.3.1]non-6-en-4-ones
US3961066 *Mar 29, 1974Jun 1, 1976Sumitomo Chemical Company, Limited6,7-Benzomorphan derivatives
US3981874 *Oct 15, 1974Sep 21, 1976Boehringer Ingelheim GmbhN-[(Methoxymethyl-furyl)-methyl]-morphinans or -6,7-benzomorphans and salts thereof
US4029798 *Jun 2, 1975Jun 14, 1977Sumitomo Chemical Company, LimitedAnalgetic composition
US4127577 *Sep 20, 1976Nov 28, 1978Sterling Drug Inc.Aminomethanobenzazocine process
US4166174 *Jun 13, 1977Aug 28, 1979Chugai Seiyaku Kabushiki KaishaAnalgesics
US4205171 *Jan 16, 1978May 27, 1980Sterling Drug Inc.Aminomethanobenzazocines and nitromethanobenzazocines
US4241070 *Oct 27, 1976Dec 23, 1980Sumitomo Chemical Company, LimitedNonhabit-forming
Classifications
U.S. Classification546/97, 564/378, 546/348, 568/312, 546/343, 546/286, 568/327
International ClassificationC07D221/26, C07D221/00
Cooperative ClassificationC07D221/26
European ClassificationC07D221/26